Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding

Pingfeng Zhang; Latifeh Azizi; Sampo Kukkurainen; Tong Gao; Mo Baikoghli; Marie Claude Jacquier; Yijuan Sun; Juha A.E. Määttä; R. Holland Cheng; Bernhard Wehrle-Haller; Vesa P. Hytönen; Jinhua Wu

doi:10.1073/pnas.2014583117

Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding

Pingfeng Zhang
, Latifeh Azizi
, Sampo Kukkurainen
, Tong Gao
, Mo Baikoghli
, Marie Claude Jacquier
, Yijuan Sun
, Juha A.E. Määttä
, R. Holland Cheng
, Bernhard Wehrle-Haller
, Vesa P. Hytönen
, Jinhua Wu^*

^*Tämän työn vastaava kirjoittaja

Kliinisen kemian yksikkö

Tutkimustuotos: Artikkeli › Tieteellinen › vertaisarvioitu

29 Sitaatiot (Scopus)

24 Lataukset (Pure)

Abstrakti

Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced β3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the β3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of β3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the β3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.

Alkuperäiskieli	Englanti
Sivut	32402-32412
Sivumäärä	11
Julkaisu	Proceedings of the National Academy of Sciences of the United States of America
Vuosikerta	117
Numero	51
DOI - pysyväislinkit	https://doi.org/10.1073/pnas.2014583117
Tila	Julkaistu - jouluk. 2020
OKM-julkaisutyyppi	A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä

Rahoitus

ACKNOWLEDGMENTS. Ulla Kiiskinen, Niklas Kähkönen, and Monica Julio Barreto are acknowledged for excellent technical help. Hongquan Zhang and Staffan Strömblad kindly provided the kindlin-1 construct. We acknowledge Prof. Janne Jänis (University of Eastern Finland) for the determination of total mass of the purified talin head proteins. M.B. and R.H.C. were supported by the NIH (grants TR002866, EB021230, CA225266, and CA198880) (R.H.C.) and National Institute of Food and Agriculture (CAD-MCB7399H) (R.H.C.). We acknowledge Academy of Finland (Grant 290506) for research funding (to V.P.H.). Biocenter Finland is acknowledged for infrastructure support. S.K. was supported by the Tampere Graduate Program in Biomedicine and Biotechnology. B.W.-H. and M.-C.J. were supported by Swiss National Science Foundation Grants 31003A_166384 and 310030_185261. P.Z., T.G., Y.S., and J.W. were supported by NIH Grant GM119560 (to J.W.) and American Cancer Society Grant RSG-15-167-01-DMC (to J.W.).

Julkaisufoorumi-taso

Jufo-taso 3

!!ASJC Scopus subject areas

General

Pääsy asiakirjaan

10.1073/pnas.2014583117Lisenssi: CC BY-NC-ND

32402.fullFinal published version, 2,47 MBLisenssi: CC BY-NC-ND

http://urn.fi/URN:NBN:fi:tuni-202101131239Lisenssi: CC BY-NC-ND

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Zhang, P., Azizi, L., Kukkurainen, S., Gao, T., Baikoghli, M., Jacquier, M. C., Sun, Y., Määttä, J. A. E., Cheng, R. H., Wehrle-Haller, B., Hytönen, V. P., & Wu, J. (2020). Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding. Proceedings of the National Academy of Sciences of the United States of America, 117(51), 32402-32412. https://doi.org/10.1073/pnas.2014583117

@article{8dc4294526af40458c1c187e074729c6,

title = "Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding",

abstract = "Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced β3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the β3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of β3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the β3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.",

keywords = "Cell adhesion, FERM domain, Integrin, NPxY motif, Talin",

author = "Pingfeng Zhang and Latifeh Azizi and Sampo Kukkurainen and Tong Gao and Mo Baikoghli and Jacquier, \{Marie Claude\} and Yijuan Sun and M{\"a}{\"a}tt{\"a}, \{Juha A.E.\} and Cheng, \{R. Holland\} and Bernhard Wehrle-Haller and Hyt{\"o}nen, \{Vesa P.\} and Jinhua Wu",

note = "Funding Information: ACKNOWLEDGMENTS. Ulla Kiiskinen, Niklas K{\"a}hk{\"o}nen, and Monica Julio Barreto are acknowledged for excellent technical help. Hongquan Zhang and Staffan Str{\"o}mblad kindly provided the kindlin-1 construct. We acknowledge Prof. Janne J{\"a}nis (University of Eastern Finland) for the determination of total mass of the purified talin head proteins. M.B. and R.H.C. were supported by the NIH (grants TR002866, EB021230, CA225266, and CA198880) (R.H.C.) and National Institute of Food and Agriculture (CAD-MCB7399H) (R.H.C.). We acknowledge Academy of Finland (Grant 290506) for research funding (to V.P.H.). Biocenter Finland is acknowledged for infrastructure support. S.K. was supported by the Tampere Graduate Program in Biomedicine and Biotechnology. B.W.-H. and M.-C.J. were supported by Swiss National Science Foundation Grants 31003A\_166384 and 310030\_185261. P.Z., T.G., Y.S., and J.W. were supported by NIH Grant GM119560 (to J.W.) and American Cancer Society Grant RSG-15-167-01-DMC (to J.W.). Publisher Copyright: {\textcopyright} 2020 mSystems. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = dec,

doi = "10.1073/pnas.2014583117",

language = "English",

volume = "117",

pages = "32402--32412",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "51",

}

Zhang, P, Azizi, L, Kukkurainen, S, Gao, T, Baikoghli, M, Jacquier, MC, Sun, Y, Määttä, JAE, Cheng, RH, Wehrle-Haller, B, Hytönen, VP & Wu, J 2020, 'Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding', Proceedings of the National Academy of Sciences of the United States of America, Vuosikerta 117, Nro 51, Sivut 32402-32412. https://doi.org/10.1073/pnas.2014583117

TY - JOUR

T1 - Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding

AU - Zhang, Pingfeng

AU - Azizi, Latifeh

AU - Kukkurainen, Sampo

AU - Gao, Tong

AU - Baikoghli, Mo

AU - Jacquier, Marie Claude

AU - Sun, Yijuan

AU - Määttä, Juha A.E.

AU - Cheng, R. Holland

AU - Wehrle-Haller, Bernhard

AU - Hytönen, Vesa P.

AU - Wu, Jinhua

N1 - Funding Information: ACKNOWLEDGMENTS. Ulla Kiiskinen, Niklas Kähkönen, and Monica Julio Barreto are acknowledged for excellent technical help. Hongquan Zhang and Staffan Strömblad kindly provided the kindlin-1 construct. We acknowledge Prof. Janne Jänis (University of Eastern Finland) for the determination of total mass of the purified talin head proteins. M.B. and R.H.C. were supported by the NIH (grants TR002866, EB021230, CA225266, and CA198880) (R.H.C.) and National Institute of Food and Agriculture (CAD-MCB7399H) (R.H.C.). We acknowledge Academy of Finland (Grant 290506) for research funding (to V.P.H.). Biocenter Finland is acknowledged for infrastructure support. S.K. was supported by the Tampere Graduate Program in Biomedicine and Biotechnology. B.W.-H. and M.-C.J. were supported by Swiss National Science Foundation Grants 31003A_166384 and 310030_185261. P.Z., T.G., Y.S., and J.W. were supported by NIH Grant GM119560 (to J.W.) and American Cancer Society Grant RSG-15-167-01-DMC (to J.W.). Publisher Copyright: © 2020 mSystems. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/12

Y1 - 2020/12

N2 - Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced β3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the β3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of β3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the β3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.

AB - Binding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin receptors induces integrin activation and clustering. These processes are essential for cell adhesion, migration, and organ development. Although the talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a truncated form has been crystallized in an unexpected, elongated form. This form, however, lacks a C-terminal fragment and possesses reduced β3-integrin binding. Here, we present a crystal structure of a full-length talin head in complex with the β3-integrin tail. The structure reveals a compact FERM-like conformation and a tightly associated N-P-L-Y motif of β3-integrin. A critical C-terminal poly-lysine motif mediates FERM interdomain contacts and assures the tight association with the β3-integrin cytoplasmic segment. Removal of the poly-lysine motif or disrupting the FERM-folded configuration of the talin head significantly impairs integrin activation and clustering. Therefore, structural characterization of the FERM-folded active talin head provides fundamental understanding of the regulatory mechanism of integrin function.

KW - Cell adhesion

KW - FERM domain

KW - Integrin

KW - NPxY motif

KW - Talin

U2 - 10.1073/pnas.2014583117

DO - 10.1073/pnas.2014583117

M3 - Article

C2 - 33288722

AN - SCOPUS:85098130104

SN - 0027-8424

VL - 117

SP - 32402

EP - 32412

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 51

ER -

Crystal structure of the FERM-folded talin head reveals the determinants for integrin binding

Abstrakti

Rahoitus

Julkaisufoorumi-taso

!!ASJC Scopus subject areas

Pääsy asiakirjaan

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